Analgesic nephropathy: renal distribution of acetaminophen and its conjugates

Acetaminophen (APAP) and its conjugates (APAP-conj) are the major metabolites of phenacetin. To study their significance in the pathogenesis of analgesic nephropathy, their concentrations in the renal parenchyma were determined in conjunction with clearance measurements in 15 dogs with inulin as a reference marker. Particular attention was given to interpretation of the mechanisms responsible for the concentrations generated within the papilla. For APAP, APAP-conj and inulin there is a significant corticomedullary gradient which is inversely related to the rate of urine flow. For inulin and APAP-conj, this gradient may be explained by their concentrations within the tubular fluid of the distal nephron. With concentration in the urine as a reference, the apparent volume of distribution of inulin within the papilla is not fixed, but varies with the rate of urine flow. Using several different types of comparison with inulin, we found that the results with APAP are consistent with its penetration by diffusion into the cellular compartment of the papilla. Dehydration leads to maximal concentrations of APAP in the urine as well as in the tubular fluid and the cells of the distal nephron. This is consistent with the kinetics of diffusion.